News this Week

Science  29 Aug 2003:
Vol. 301, Issue 5637, pp. 1164
  1. ENERGY RESEARCH

    Heated Debate Ahead on U.S. Energy Agenda

    1. David Malakoff

    Science advocates are hoping that a controversial federal energy bill will give research a jolt. When Congress returns from its summer recess next week, it will face two versions of a mammoth measure packed with science-related provisions on everything from increased research spending to a new energy research czar. But disagreements over power grid regulation, oil drilling in Alaska, and other issues could still doom any attempted compromise.

    Two years ago, the Bush Administration drew up a controversial energy strategy that included recommendations to reenergize nuclear power, open Alaska's Arctic National Wildlife Refuge to oil drilling, and boost research into fusion energy and hydrogen-powered cars. Congress couldn't agree on a final version of the subsequent energy legislation last year, but this fall negotiators hope that the memory of this month's massive blackout will spur legislators to reconcile a bill passed by the House of Representatives in April with a Senate version approved 31 July. The science community “is pretty much a bystander in this endgame; it is truly going to be decided by power politics,” says one House aide.

    Blossoming debate.

    Drilling in the Arctic National Wildlife Refuge (ANWR) is one of many controversial issues under discussion.

    PHOTO CREDIT: DEAN BIGGENS/U.S. FISH AND WILDLIFE SERVICE

    Even so, science lobbyists hope to preserve a host of provisions now on the table. Both bills, for instance, call for significant spending increases for the Department of Energy's (DOE's) Office of Science, which has seen its research budget stagnate at about $3 billion in recent years. The House bill would authorize the office to spend up to $5.7 billion in 2007, whereas the Senate bill would top out at $5 billion in 2006. Although the language doesn't require Congress to provide the money, backers say it would strengthen their efforts to double DOE's science budget.

    More controversial is how best to manage the department's science programs. The Senate wants to create a new position, undersecretary for energy and science, to raise the research program's profile. The House, meanwhile, calls for a new external advisory body to reach the same goal and help set overall research priorities. Conferees could bite on both ideas or neither one, says lobbyist Toby Smith of the Association of American Universities in Washington, D.C.

    View this table:

    Uncertainty also surrounds a Senate call for an array of new climate change research efforts, including a national registry of greenhouse gas emissions. The House bill is silent on that idea and on a Senate plan for a $30 million climate change research center in Barrow, Alaska. The House would open the Arctic refuge to oil exploration, something that a majority of senators have vowed to prevent. The House also would exempt from regulation an oil-drilling technique known as “hydraulic cracking,” whereas the Senate wants geoscientists to study the practice, which boosts production by pumping water, sand, and chemicals into the ground.

    Despite their disagreements, legislators are united on their need for guidance from the U.S. National Academies. The two bills call for the government's premier science advisory body to study more than a dozen issues, from using ocean waves to generate energy to promoting bicycle transport.

  2. SCIENCE POLICY

    Feds Ask a $100 Billion Question

    1. Jeffrey Mervis

    Is the U.S. government taking a 20th century approach to funding 21st century science? That's the question that a new federal panel will be asking the community at four fall workshops. The goal is to improve how the federal government manages its $100- billion-a-year investment in basic and applied research, without adding to the tab.

    Research universities depend on a steady flow of federal dollars. But the myriad strings attached—rules on everything from disposing of hazardous wastes to protecting the rights of human subjects, not to mention keeping track of the money—create a constant source of tension. The interagency panel will examine whether the current system serves increasingly collaborative and interdisciplinary research, whether agencies can adopt common practices, and whether the administrative burden can be eased without a loss of accountability. “We're not interested in a laundry list of complaints,” says panel co-chair Connie Atwell of the National Institutes of Health (NIH). “We want data, not hearsay or opinion.”

    The point person for this new effort is Geoff Grant, a longtime NIH grants administrator who for the last 5 years has managed Stanford University's research portfolio. Grant will work at the White House Office of Science and Technology Policy, where he will be on loan from a senior management post at the National Science Foundation. “I've seen it from both sides,” says Grant, who starts 22 September. “Now I have the chance to make the relationship even better.”

    Workshops are set for 27 October in Berkeley, California; 12 November in Minneapolis; 17 November in Research Triangle Park, North Carolina; and 9–10 December in Washington, D.C. For more information, see the 6 August Federal Register (p. 46631) or e-mail nstc_rbm{at}ostp.eop.gov Grant says that White House officials are hoping to have an impact “within the next 1 to 2 years.”

  3. LONGEVITY RESEARCH

    In Vino Vitalis? Compounds Activate Life-Extending Genes

    1. Stephen S. Hall*
    1. Stephen S. Hall is the author of Merchants of Immortality: Chasing the Dream of Human Life Extension.

    According to Greek mythology, the hapless mortal Tithonus mistakenly asked the goddess Eos to confer eternal life rather than eternal youth, and he thus found himself condemned to immortal decrepitude. A new report suggests that if Tithonus had cut a side deal with Dionysus, the god of wine, he might have fared much better.

    The study knits together threads of recent molecular research on aging, the venerable antiaging strategy of calorie restriction, and, surprisingly, the health benefits of moderate tippling. David Sinclair of Harvard Medical School in Boston and colleagues identify several naturally occurring small molecules that extend the life of yeast cells by approximately 70% and offer some protection to cultured human cells exposed to radiation. The molecules activate genes known to extend life span in laboratory animals. They belong to a family of chemicals known as polyphenols, some of which are prominent components of grapes, red wine, olive oil, and other foods.

    The work by Sinclair and collaborators at the biotech firm BIOMOL Research Laboratories in Plymouth Meeting, Pennsylvania, including Konrad Howitz, is the latest in an increasingly hot field exploring the molecular biology of calorie restriction, a phenomenon first demonstrated in the 1930s. Laboratory rats fed a limited diet live about 40% longer than normal and are resistant to many chronic illnesses typical of aging. The observations have been replicated in yeast, fruit flies, nematodes, fish, spiders, and mice, with hints from ongoing experiments that they hold true for primates. These findings have fueled interest in understanding how calorie restriction works—and an increasingly spirited search for molecules that might mimic the process without requiring a draconian diet.

    Research in the Massachusetts Institute of Technology laboratory of Leonard Guarente, for example, has shown that increasing the activity of a single gene, called SIR2, can extend the life span of yeast. And without the gene, calorie restriction doesn't prolong life. The new research shows that certain molecules activate SIR2 in yeast, as well as an analogous gene, SIRT1, in human cells. Sinclair says that preliminary data from experiments in nematodes and fruit flies are “encouraging,” in terms of whether similar activation of SIR-like genes, known collectively as sirtuins, can occur in those organisms, too. The study “establishes that you can get activation of SIR2,” says Guarente, who has co-founded a company called Elixir Pharmaceuticals, which is searching for drugs that target the Sir pathway.

    Fountain of youth juice.

    Red wine and grapes contain a compound that prolongs life in yeast.

    CREDIT: BOB NICHOLS/USDA

    Working with colleagues at Harvard, BIOMOL researchers began screening a library of compounds about 2 years ago for molecules that trigger SIRT1 activity. The initial screen yielded two polyphenols, quercetin (found in apples and tea) and piceatannol. The team then searched for other molecules with similar structures. That canvass yielded another 15 compounds, the most potent of which turned out to be resveratrol, found in grapes and red wine. It increased SIRT1 activity 13-fold, the team reports online 24 August in Nature.

    Resveratrol's SIRT1-activating power adds another dimension to the work, because it suggests a link to the so-called French paradox, the observation that despite a high-fat diet, people in France suffer about 40% less cardiovascular disease than expected; epidemiologists have linked this effect to the moderate consumption of red wine. Sinclair and colleagues speculate that these benefits may derive from activation of SIR-like genes. Increased SIRT1 activity in human cells seems to blunt the activity of the tumor-suppressor gene p53, blocking programmed cell death. Sinclair suggests that the SIR-activating compounds buy time for cells to heal themselves rather than commit suicide.

    In addition to its immediate implications for aging and life extension, the new work bolsters the notion that there is an evolutionarily conserved mechanism to stall the aging process during times of stress, such as when food is scarce. It also raises the possibility that the sirtuin-activating compounds reflect an interaction between plant and animal species. According to this hypothesis, which Sinclair calls “xenohormesis,” plants increase their own production of polyphenols in response to environmental stresses such as drought, and that message of impending crisis may be passed on to animals that eat the plants. “Other unrelated, nonplant species can get chemical clues from the plant world,” Sinclair says, “which causes them to mount their own defense response.” Alternatively, he adds, the plant compounds may simply be similar to analogous, unidentified molecules in human biology.

    Richard Weindruch of the University of Wisconsin, Madison, who is conducting calorie-restriction experiments in monkeys and other animals, applauds the new report but adds, “I think one needs to be very cautious about making dramatic leaps from the yeast model into mammals.” He notes that it was unclear, for example, whether resveratrol affected the aging process in the kind of cells in the heart and brain that are particularly susceptible to degeneration with age.

    “It's kind of romantic that red wine contains something that could extend your longevity, don't you think?” says Cynthia Kenyon, who researches aging at the University of California, San Francisco, after seeing the data presented at a meeting in Switzerland last week. But the results have not caused Sinclair to renegotiate his relationship with Dionysus. “I'd already increased my red wine consumption prior to this discovery,” he confesses with a laugh.

  4. WILDLIFE CONSERVATION

    U.N. Joins Russia's Fight to Save Western Pacific Salmon

    1. Paul Webster*
    1. Paul Webster is a writer based in Moscow.

    PETROPAVLOVSK-KAMCHATSKIY, RUSSIA—The motorboat rounds a bend, drifting along the Avacha River as two hooded men haul aboard a net full of egg-laden salmon. Standing in a pair of battered hip waders while observing salmon runs last week, Oleg Pustovit can hardly contain his anger. “Red caviar poachers are permanently destroying these spawning grounds,” fumes Pustovit, an ichthyologist at the Wild Salmon Center (WSC) in Portland, Oregon. The genetic integrity of salmon populations in the rivers of Russia's far eastern Kamchatka Peninsula, he predicts, “will be ruined … within a decade,” unless something is done to curtail the poaching.

    The rest of the world agrees. This week the United Nations Development Programme (UNDP) launched a 5-year, $13 million initiative to promote habitat conservation in four major Kamchatka rivers. The effort includes research funds as well as support for authorities to crack down on poachers by beefing up conservation and enforcement. “The new money will go a long way to beat back the poachers and to help [Russian scientists] pursue many unanswered questions” about species diversity, says conservation ecologist Jack Stanford of the University of Montana, Missoula.

    With six oceangoing and two freshwater species, Kamchatka boasts the greatest diversity of salmonids in the world: An estimated 25% of all wild salmon in the Pacific spawn here. For decades the salmon were protected by Kamchatka's status as a restricted military zone during the Cold War. Since the collapse of the Soviet Union, however, a depressed economy has turned an unknown number of the peninsula's 350,000 residents into poachers. Russia's Northeastern Fisheries Committee (Sevestrybvod) estimates that poachers in Kamchatka ship out $1 billion worth of salmon caviar annually; the 300 to 400 grams of eggs that each female carries can fetch up to $50. “Enormous ecological damage is being done,” asserts Alexander Chistyakov, vice governor of the Kamchatka region.

    Poacher paradise?

    A new U.N. initiative will help preserve salmon habitat in four key Kamchatka rivers, including the Zhupanova.

    CREDIT: GUIDO RAHR/WILD SALMON CENTER

    Corrupt enforcement poses another threat. Igor Sobota, a senior inspector at Sevestrybvod, which cracks down on poachers in military-style operations staged from boats and battered Soviet-era helicopters, claims that low salaries make it hard for officials at the federal fisheries protection service to resist bribes. “Poaching has become big business,” he says, “with many operations using helicopters and ships to send tons of caviar to markets in Asia, Russia, and Europe daily.”

    The new UNDP program will boost the budgets of antipoaching programs and make them more effective by bringing together the Kamchatka and Koryak governments, Sevestrybvod, Moscow State University's ichthyology department, and WSC in a bid to conserve salmon habitat in the four rivers. The initiative follows on the heels of a $16 million UNDP program for improved wildlife protection and research in the region (Science, 13 September 2002, p. 1787).

    At WSC's Kol River research station, 40 kilometers from the Sea of Okhotsk and deep in Kamchatka's rugged west coast wilderness, Moscow State ichthyologist Kirill Kuzishchin analyzes salmon skull samples in a laboratory inside a large canvas tent beside a river jumping with salmon. UNDP money will enable Kuzishchin and his colleagues to undertake radiotagging and DNA sampling for experiments that could explain whether the salmon randomly or purposefully choose freshwater and saltwater habitats and why they spawn where they are born. “These are some of the biggest questions,” says Kuzishchin. “We feel a lot more confident now that we will find the answers.”

  5. PALEONTOLOGY

    Ancient Weapon of Mass Destruction: Methane Gas?

    1. Erik Stokstad

    The demise of the dinosaurs may grab all the headlines, but paleontologists have long pondered an even bloodier murder mystery: What wiped out the vast majority of species on land and in the ocean 186 million years before Tyrannosaurus and company bit the dust?

    Now, two papers argue that methane gas did the dirty work—although they disagree about how. In the September issue of Geology, chemical engineer Gregory Ryskin of Northwestern University sketches an apocalyptic scenario in which methane erupted from the sea floor and incinerated land dwellers as it exploded. Meanwhile, in The Geological Society of America Bulletin, three paleontologists suggest that the gas attack would have essentially suffocated its victims. “They're exciting and spectacular ideas,” says marine geologist Paul Wignall of Leeds University, U.K. But he and other experts aren't ready to embrace them just yet.

    Scientists have long tried to pin the Permian-Triassic extinction on global warming, perhaps spurred by erupting volcanoes. Methane, CH4, played a supporting role in that scenario, helping account for a shift in carbon isotopes found in rocks from that period. As the oceans warmed, the story went, they seeped methane into the atmosphere, where it turned into carbon dioxide and exacerbated the warming trend over 10,000 years. But many researchers doubted that climate change alone could have so devastated life on land.

    Ryskin's theory puts methane front and center. The idea came to him while he was lecturing to his engineering students about Lake Nyos in Cameroon, where clouds of lethal carbon dioxide had suddenly bubbled out of the deep waters, forming a cloud that killed 1800 villagers in 1986. About 10,000 gigatons of methane would be needed to account for the carbon-isotope shift, Ryskin reckoned—a whopping amount, yet easily dissolved in the oceans. An earthquake or submarine volcanic eruption could have created bubbles that would have lowered the density and pressure of the water as they rose, causing the ocean to release even more dissolved gas. Over a few days, massive amounts of methane would have entered the atmosphere and, detonated by lightning, fueled widespread fires whose products could have triggered either a nuclear winter or global warming, Ryskin says.

    Hunkered down.

    Burrowing animals, such as these Thrinaxodon, seem to have survived the end-Permian extinction better.

    CREDIT: IZIKO/SOUTH AFRICAN MUSEUM

    Some scientists have trouble imagining such a conflagration. “I just don't find compelling evidence that the methane levels needed were present in the Permian ocean,” says geochemist Lee Kump of Pennsylvania State University, University Park. He says bacteria would have degraded the methane before it could reach dangerous levels. Also missing, he and Wignall note, is any sign of vast conflagrations at the boundary.

    Enter the second theory, which does not require a firestorm. Studying Permian-Triassic soils from South Africa, Gregory Retallack of the University of Oregon in Eugene and colleagues saw no evidence of climate change drastic enough to explain the extinctions. They, too, thought of oceanic gas. Other researchers had suggested that the voluminous release of carbon dioxide could have harmed marine animals. Methane, Retallack's team concluded, could have affected land animals as well, by lowering the relative amount of oxygen in the air enough to trigger pulmonary and cerebral edema. “The reptiles died of mountain sickness,” Retallack says.

    Retallack—along with Roger Smith of the South African Museum in Cape Town and Peter Ward of the University of Washington, Seattle—points out that many survivors of the extinction were built to cope with low oxygen levels. The most abundant one, a dog-sized creature called Lystrosaurus, was a burrower with thick ribs and a barrel chest for efficient breathing. Smith notes that amphibians, which survived the extinction relatively well, also could have dealt with the changing air by burrowing into lakebeds.

    “I think it's a really neat story,” says Christian Sidor, a paleontologist at the New York College of Osteopathic Medicine in Old Westbury. “It's very imaginative.” He notes that other survivors are also found in burrows, such as a group of possible turtle relatives called the procolophonoids. Michael Benton of Bristol University, U.K., on the other hand, suspects that it may just be chance that Lystrosaurus survived the crisis. And Sidor points out that the evidence so far only comes from part of the Permian world: “It's going to take more work to show it's worldwide.”

    Retallack and his team hope that a trip this fall to the Trans-Antarctic mountains will bolster their case. “I don't think the atmosphere caught fire, but it was pretty hellish,” he says.

  6. BIODEFENSE FACILITIES

    Suit Targets Two DOE Labs

    1. David Malakoff*
    1. With reporting by Martin Enserink.

    Two watchdog groups want to prevent the Department of Energy (DOE) from expanding its biodefense research. This week, Nuclear Watch of New Mexico and Tri-Valley CAREs of California asked a federal judge to halt construction of two new biosafety level 3 (BSL-3) labs, claiming that the department hasn't conducted adequate environmental and nonproliferation studies. But DOE says that its existing studies are adequate and have shown that the labs will have minimal impact.

    Since the 11 September terrorist attacks, the U.S. government has been moving to expand the number of high-containment labs where biodefense researchers can work with hazardous agents. The United States now has about a half-dozen of the most secure BSL-4 facilities and dozens of less restrictive BSL-3 laboratories; but so far, DOE has had only BSL-2 labs.

    The new BSL-3 spaces now under construction at Los Alamos National Laboratory in New Mexico and Lawrence Livermore National Laboratory in California would enable the agency to work with agents such as anthrax and plague. DOE gave the go-ahead to the $5.5 million project last year, after concluding that neither facility would have a “significant impact” on the environment. Both labs could open their doors next year.

    But in a lawsuit filed 26 August in San Francisco, the two groups charged that DOE glossed over site-specific risks, such as how the labs might deal with an accidental spill or an earthquake, and failed to tally the potential broader impacts of its entire bioterror program. Nor did it consider whether conducting biodefense research at secretive nuclear weapons labs could foster distrust abroad and endanger compliance with the Biological and Toxin Weapons Convention, says Marylia Kelley, director of Tri-Valley CAREs, who believes that biodefense work should be done by a health agency.

    Activists are trying to block or slow down other proposed BSL-3 and BSL-4 labs at various sites around the country, including the University of California, Davis; the University of Texas Medical Branch in Galveston; and National Institutes of Health (NIH) facilities in Bethesda, Maryland, and Hamilton, Montana. Opposition is expected to increase when NIH awards the first of several major construction grants next month.

    “There's more noise about this now than there ever was,” says Karl Johnson, a former chief of the Centers for Disease Control and Prevention's Special Pathogens Branch and a consultant to several of the proposed labs. He predicts that lab managers and researchers elsewhere will be watching the DOE suit “very, very carefully.”

  7. SPACETIME

    Einstein 1, Quantum Gravity 0

    1. Adrian Cho*
    1. Adrian Cho is a freelance writer in Grosse Pointe Woods, Michigan.

    For 5 years, physicists have hoped that a flaw in Einstein's special theory of relativity might reveal that space and time aren't smooth at the smallest scale, but fuzzy and foaming. Now, that tantalizing prospect has vanished in a puff of gamma rays. Two independent measurements of cosmic gamma rays show that Einstein was right after all—and that current plans to detect the foam are doomed. “The results rule out these possibilities on empirical grounds,” says Floyd Stecker, a theoretical astrophysicist at NASA's Goddard Space Flight Center in Greenbelt, Maryland.

    The frothiness of space and time is predicted by many theories that attempt to meld Einstein's theory of gravity and quantum mechanics. Physicists hoped to detect it by finding a hole in Einstein's dictum that it is meaningless to say an object is moving or stationary relative to the universe, a principle known as Lorentz invariance. One consequence of the principle is that all particles of light, or photons, travel through empty space at the same speed regardless of how much energy they pack.

    In recent years, however, various quantum gravity theories have suggested that Lorentz invariance might not hold. In that case, a photon's speed would vary with its energy, so that light of different wavelengths would travel at slightly different rates. That would make intuitive sense, says Giovanni Amelino-Camelia, a theoretical physicist at the University of Rome, La Sapienza. After all, when light flows through water or air, its speed depends on its energy; perhaps foamy spacetime has the same effect.

    Researchers might spot the tiny differences in high-energy light that had traveled far enough for faster photons to pull ahead of slower ones. In 1998, Amelino-Camelia and colleagues suggested that astronomers scrutinize gamma ray bursts—enormous extragalactic explosions that last only seconds—for evidence that rays of different energy reach Earth at different times. Such data will be collected by NASA's Gamma-ray Large Area Space Telescope (GLAST).

    But 2 years before the launch of GLAST, Stecker and others have shown that Lorentz invariance holds firm. Stecker and colleagues studied gamma rays from the hearts of the galaxies Markarian 421 and Markarian 501, some 450 million light-years from Earth. En route the rays pass through a thin haze of infrared photons that fill intergalactic space. If Lorentz invariance were violated, the gamma rays would zip right through the haze. According to special relativity, however, the highest energy gamma rays should collide with the infrared photons to make electron-antielectron pairs. This process should soak up gamma rays above a well-defined cutoff energy—just what the researchers observed, Stecker reports in a paper to be published in the journal Astroparticle Physics.

    Gamma rays from the Crab Nebula also bear out Einstein's theory, gravitation theorist Ted Jacobson and colleagues at the University of Maryland, College Park, report in this week's issue of Nature. The rays come from extremely energetic electrons spiraling in the magnetic fields inside the gargantuan cloud of gas. If Lorentz invariance were violated, the electrons would slam up against a virtual speed limit slower than the speed of light. From the energy of the gamma rays, however, Jacobson and colleagues deduced that the electrons were traveling within a 10-billion-billionth of the speed of light—even stronger evidence that Einstein was right.

    A loophole in special relativity “would have been great,” Jacobson says. “We're desperate for some observational input into quantum gravity.” But the new results are just that, says Lee Smolin, a theoretical physicist at the Perimeter Institute for Theoretical Physics in Waterloo, Canada. “I think it's great,” Smolin says, “because it means that physically plausible hypotheses are being confronted with experimental data.”

    The results sink several quantum gravity theories, but not string theory, which assumes that every particle is a little loop of “superstring,” or a leading alternative called loop quantum gravity (Science, 8 November 2002, p. 1166). Because neither requires violations of Lorentz invariance, both theories remain viable for now—and quantum gravity remains undetectable.

  8. BIOTECHNOLOGY

    Yeast Engineered to Produce Sugared Human Proteins

    1. Robert F. Service

    Protein-based drugs are hot. The upstart rivals to traditional small-molecule therapeutics already account for $30 billion annually in sales, a number expected to double by the decade's end. Still, biotech and pharma companies often struggle to turn their proteins into medicines. One major stumbling block is that most proteins are decorated with small groups of sugar molecules, and the wrong sugars can trigger a dangerous immune reaction. Mammalian cell cultures can tack on sugars correctly, but they're finicky and costly. Now researchers have found what promises to be a cheaper way to produce sugared proteins correctly—with yeast.

    On page 1244, a team of researchers led by Tillman Gerngross, a chemical engineer and molecular biologist at Dartmouth College in Hanover, New Hampshire, and the chief scientist at GlycoFi in Lebanon, New Hampshire, reports engineering yeast cells to make proteins with sugar attachments found on human proteins. “This is something people have been trying to do for a long time,” says Kelley Moremen, a biochemist at the University of Georgia in Athens. Not only could the new process ease the manufacture of existing protein therapeutics —and thus drop their price—but it could also speed the search for new so-called glycoprotein drugs, because researchers could easily attach different sugars to screen for the most effective combination.

    Sugars help proteins fold properly and remain stable when circulating in the blood. But different species attach a widely varying combination of sugars in a light scaffold, creating patterns that immune cells use to help them distinguish host proteins from invaders. Yeast cells, for example, decorate proteins with the sugar mannose, whereas human cells add sugars such as galactose and sialic acid. More than a decade ago, researchers began producing protein therapeutics in ovary cells from Chinese hamsters, which tack on the appropriate sugars for mammals such as humans. But these cell lines often produce only modest amounts of protein and can be tricky to keep healthy.

    Sugar solution.

    A light scaffold of sugars (gray and red, top) surrounds most human proteins. Engineered yeast (bottom) can now make the correct attachments.

    CREDITS: (TOP TO BOTTOM) NATIONAL CENTER FOR BIOTECHNOLOGY INFORMATION; JENNIFER LABERGE/GLYCOFI INC.

    Producing proteins in yeast would be a lot simpler. In both yeast and humans, proteins are constructed in the endoplasmic reticulum, decorated with a complex of mannose and other sugars, and eventually shipped to the Golgi apparatus for further processing. In yeast, additional mannose groups are then added. In humans, however, an enzyme called mannosidase chops off the mannose groups, and other enzymes tack on a variety of other sugars. Several research teams had reasoned that if yeast cells could be engineered to express mannosidase, the cells wouldn't produce the mannose-rich sugar complexes that are so immunogenic to humans. But early attempts failed.

    Gerngross and his colleagues suspected that mannosidase in engineered yeast wasn't finding its way to the Golgi apparatus. Many proteins harbor short peptides that act as cellular postal codes, directing their cargo to the appropriate destination. Engineered yeast's mannosidase still sported the wrong code, the New Hampshire researchers found. They fiddled with these codes, inserted a more efficient mannosidase, and engineered a yeast strain with glycoproteins containing far fewer mannose groups, they reported in the 29 April Proceedings of the National Academy of Sciences.

    Still, their job was only half done; the resulting proteins hadn't been decorated with the sugars commonly found in humans. In the current work, Gerngross's team linked peptide cell targeting codes to a series of enzymes that attach sugars found on human proteins and then added the genes for these hybrids to mannosidase-producing yeast. The combination worked like a charm, producing large amounts of humanlike proteins.

    In fact, it worked so well that Moremen says he was somewhat astonished. The engineered yeast not only turn out introduced proteins in human form, they also make the same modifications to all their own cellular proteins. Moremen says he expected the changes to be debilitating to the yeast, but they don't appear the worse for wear. “Everybody is mystified by that,” Moremen says, adding that he suspects that several research groups will now focus on that problem.

    The humanized yeast proteins still don't express the sugar sialic acid, whose presence helps proteins evade clearance mechanisms in the body and circulate longer. If the team adds that machinery to yeast as well, Moremen says he believes the technique could be broadly useful to produce cheaper protein therapeutics. That could add even more heat to a red-hot field.

  9. GUNTHER VON HAGENS

    Anatomy's Full Monty

    1. John Bohannon
    1. John Bohannon is a writer based in Paris. With reporting by Ding Yimin and Xiong Lei of China Features in Beijing.

    Gunther von Hagens developed a way to preserve tissue by replacing fluids with polymers. His “plastinated” body exhibits are drawing vast crowds. Is he the savior of anatomy, the “Disney of Death,” or both?

    DALIAN, CHINA—The cavernous chamber is as chilly as a morgue. Its enormous garage door has been left ajar to allow chemical fumes to escape into the frigid winter air. Within the fluorescently lit space, four Chinese technicians wearing teal smocks and rubber gloves huddle around the torso of a figure lying on a long steel trolley. A fifth technician, a young woman perched on a stool next to the trolley, cradles a pasty hand in hers and delicately peels away the skin of the palm with tweezers. She looks up from her work and smiles shyly. Flaying the skin from a human body without damaging the underlying tissues demands hours of painstaking work. The team makes steady progress, centimeter by centimeter, without a whisper. There is extra impetus today because, as everyone has heard, “Gunther is coming.”

    At least every 6 weeks, their German boss, anatomist-entrepreneur Gunther von Hagens, makes a rush tour and convenes a meeting of all employees. Perhaps the remaining skin can be stripped from this cadaver before his arrival. But before the glossy tendons of the hand can be exposed, the bunker is echoing with greetings as Von Hagens appears, zipping from table to table with his Chinese translator in tow. Approaching the trolley with a toothy grin, Von Hagens nods approvingly.

    Like the dozens of plastic-wrapped bodies stacked by forklift on metal shelves along the walls, this corpse is destined not for the grave but for the public gaze. Through a process invented by Von Hagens called plastination (see sidebar), the body's decay-prone juices will be replaced by resilient plastics and its limbs permanently fixed in a position of his choosing for display in the traveling anatomy exhibit called Body Worlds (Science, 29 March 2002, p. 2359). So far, 50 whole plastinated bodies and 400 body parts—ranging in size from a torso to the anvil of the inner ear—have been viewed up close by 12.6 million people at exhibits in seven countries in Europe and Asia.

    Face to face.

    Some 12.6 million people have visited exhibits of Gunther von Hagens's work, getting a close-up view of the human body, including the inside of the head (bottom).

    CREDITS: G. VON HAGENS/INSTITUTE FOR PLASTINATION, HEIDELBERG, GERMANY. ALL PHOTOGRAPHS: COPYRIGHT INSTITUT FÜR PLASTINATION, http://www.koerperwelten.com/

    Von Hagens sees himself as the savior of anatomy, a science he claims has lost touch with a public frightened by limp body parts floating in jars. Plastination, he believes, can restore “the beauty beneath the skin.” But many academics accuse Von Hagens of trampling on human dignity and damaging the public perception of medical science. “Von Hagens's exhibition raises some very grave concerns about consent,” says Sandy Thomas, director of the Nuffield Council on Bioethics in London, because some body parts on display in Body Worlds were plastinated without consent. Von Hagens is a “showman who uses the cover of science to reap millions from voyeuristic audiences,” seethes Tom Shakespeare, a sociologist at the University of Newcastle upon Tyne, U.K.

    Von Hagens's bravado may be put to the test next year with his plans to tour Body Worlds through the United States, in part because of laws governing the use of human bodies. He explored the option of bringing his bodies to Florida in 1998, but the state's anatomy board voted to block the entry of his cadavers. But Von Hagens remains unfazed. He is confident that people will come around to his point of view sooner or later.

    Fantastic plastic

    Becoming the “Walt Disney of Death,” as a commentator on a BBC documentary called him, is a relatively recent twist in the life of Gunther von Hagens. Once upon a time in the communist East Germany of the 1960s, he was just another hard-working medical student. Along with many of his fellow students at the University of Jena, Von Hagens was arrested for protesting against the invasion of Prague by Warsaw Pact troops in 1968, and soon after he was locked away for trying to escape to West Germany.

    By a stroke of luck, 2 years later Von Hagens was among a group of political prisoners whose freedom was bought by the West, allowing him to finish his medical doctorate at the University of Heidelberg in 1975. The young and restless Von Hagens then became the research assistant of Wilhelm Kriz, a specialist in kidney pathology and now the director of the university's Institute for Anatomy and Cell Biology.

    While preparing thin slices of kidney, Von Hagens began innovating. The standard protocol of embedding the organ within a block of paraffin and then carefully cutting it into smaller sections seemed like “too much wasted effort” to him. A moment of inspiration in the local butcher shop, he says, led to a method to impregnate organs with polymers from within and then cut them with a deli meat slicer—and plastination, as he dubbed it, was born. Although those early specimens looked “anything but promising,” he was hooked.

    For Von Hagens, who names Thomas Edison as his archetype, plastination became not just his academic passion but also a business venture. Convinced of its potential, he obtained a handful of patents related to plastination and sank a sizable chunk of his own money into starting up a company in 1980 to sell the polymers. The risk paid off. After describing the technique in a few papers and at conferences, Von Hagens generated a flurry of enthusiasm among anatomical technicians. By 1982, biennial conferences were being organized by the International Society for Plastination, which began publishing its own peer-reviewed journal in 1987.

    Against the tide.

    Von Hagens, wearing his trademark hat and waistcoat, puts the finishing touches on plastinated bodies posed as swimmers.

    CREDIT: G. VON HAGENS/INSTITUTE FOR PLASTINATION, HEIDELBERG, GERMANY

    In those early days, says Ronald Wade, one of the first Americans to become licensed by Von Hagens's company as a plastinator and who is now director of the Anatomical Services Division at the University of Maryland School of Medicine in Baltimore, “it was kind of a Von Hagens admiration society.”

    The creative awakening for Von Hagens came one late night in 1988 when he encountered an awestruck janitor staring at some plastinated body parts. Until then, plastination had been a purely academic pursuit; it had hardly occurred to him that the public might be fascinated by plastinated anatomy. But a modest exhibit of plastinated specimens in the small German city of Pforzheim that year proved to be a minor hit.

    Why stop at body parts, wondered Von Hagens? Why not plastinate an entire human body so it can stand upright and stare back at eye level? By 1993, he had overcome the technical hurdles to making whole-body specimens and was selling them to medical institutions as teaching aids. But he found it difficult to convince universities and museums that the general public would not simply be repulsed. Then Tatsuo Sakai, an anatomist at Juntendo University in Japan, invited Von Hagens to stage an ensemble of plastinated bodies in Tokyo in 1996. To their amazement, more than 400,000 people squeezed through the doors in 2 months.

    “Everything changed for me after Japan,” says Von Hagens. His 1997 exhibit at a science museum in Mannheim, Germany, became so popular that the city allowed the doors to remain open 24 hours a day to reduce the enormous queues outside. Von Hagens returned twice to Japan before touring his plastinated bodies through Austria, Switzerland, and back through Germany. He then jumped the English Channel to London, where the long-extended exhibition finally closed its doors in February after 11 months. An exhibit that has been going on since April 2002 in Seoul, South Korea, has been the most successful yet, with over 2 million visitors so far. And since March of this year, Von Hagens has been running a simultaneous exhibition in Munich, Germany.

    Body Worlds has made Von Hagens a rich man. But he has much bigger plans. “I'm a monomaniac,” he admits, with plans to keep expanding the number of specimens until he can tour three simultaneous exhibits around the world and eventually create a permanent Museum of Man, ideally in Germany. To achieve this, Von Hagens says he will need thousands of bodies. That's why he has plowed 90% of his profits into the facility in Dalian, a cluster of pink concrete buildings overlooking Xinghai Bay that he calls Plastination City. Here, 240 kilometers from the North Korean border, 200 fresh-faced Chinese technicians, most of them recent graduates of Dalian Medical University, can plastinate dozens of bodies at once with assembly-line efficiency.

    Updating anatomy

    Before gathering the flock for a company meeting, Von Hagens wants to check on the progress of his latest bodily inventions. He trots in leather sandals with surprising speed through the underground corridors connecting the buildings of Plastination City, the regular pace of a man who is constantly on the move and keeps no office. “I like to wake up and not know which country I am in,” he says.

    The inside of Bunker-2 is like the studio of a Renaissance sculptor: Dozens of technicians tinker with human figures held in various poses, pausing periodically to consult anatomical illustrations. Von Hagens moves between groups of white-coated technicians, standing out like a raven over snow in his black leather vest and trademark dark fedora. Von Hagens relishes eccentricity, claiming that “an unusual outward appearance fosters nonconformist thinking,” but he also dons the hat as a nod to the tradition of Renaissance anatomists who wore hats as a mark of their profession.

    Modern-day anatomists are divided over Von Hagens's creations. Colin Stolkin, an anatomist at King's College London, notes that Body Worlds has had greater attendance than any human anatomical display in history. He himself took many groups of medical students to London's Body Worlds exhibit. “Von Hagens's dissections are outstanding,” enthuses Stolkin. But Harold Ellis, a surgeon and celebrated medical lecturer at University College London, dismisses the specimens in Body Worlds as no better than “the excellent, anatomically correct models made of plastic” that he uses for teaching. Ellis criticizes the exhibition for being a “shock provider” rather than an educational effort, pointing out several careless errors in its anatomical labeling.

    Shock tactics.

    Von Hagens has been criticized for sensationalism by plastinating bodies in striking poses.

    CREDIT: G. VON HAGENS/INSTITUTE FOR PLASTINATION, HEIDELBERG, GERMANY

    Others too are suspicious of Von Hagens's educational aims. “It's a wonderful opportunity to see what's under your hood,” says Donald Jenkins, an anatomist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, but “I run into problems with the exhibitionist style.” Jenkins was particularly turned off by a public autopsy Von Hagens performed in November 2002, parts of which were broadcast on British television (Science, 6 December 2002, p. 1881). It amounted to nothing but a “publicity stunt” for Body Worlds, he says.

    “What's wrong with sensationalism?” counters Von Hagens. In today's media-saturated world, anatomy needs a little shock and awe, and some humor, just to get people to walk through the door and pay attention, he says. And besides, Body Worlds is a benefit to public health, Von Hagens argues, because it includes comparisons of healthy and diseased bodies. On the basis of polls of people before and after visiting Body Worlds—conducted independently by Ernst Lantermann, a psychologist at the University of Kassel in Germany—Von Hagens claims to have helped persuade millions of people to smoke less, eat better, and exercise more. What could be wrong with that?

    A question of consent

    Aside from questions of taste and educational value of the Body Worlds exhibits, the biggest question his critics have raised is, Where do all the bodies come from? Some have charged that Von Hagens established himself in Dalian to ensure a steady flow of cadavers from the Chinese government, the world's number one executor of criminals. But he vehemently denies the charge. “The opposite is true,” he says. “In China there is an even greater taboo on dead bodies than in the West.” Von Hagens, who was a visiting professor at Dalian Medical University between 1994 and 1995, insists that he set up here because he was invited to do so by the university. And it seemed a wise choice because of the skill of local anatomists. Von Hagens has been able to employ 200 “excellent” anatomists for the dissecting tables of Plastination City. Of course, their roughly $280 monthly salary—about twice that of typical Dalian medical graduates—means he can attract the talent for a bargain price.

    Foreseeing that he would come under fire about the source of the bodies used for plastination, Von Hagens says he set up a body donation program in Germany as early as 1982. Von Hagens says that over 5000 donors have signed a contract—revocable at any time during life—which gives him consent to dissect, plastinate, and publicly display their bodily remains. “I now receive on average a body a day,” he says. According to Von Hagens, some 90% of donated bodies are German, but he declines to name the national origin of the remainder.

    This lack of transparency has prompted some to dig deeper. Last year a group of German journalists investigated the trail of bodies leading to his Heidelberg facility, from which bodies are transported to Dalian in shipping containers. The path took them to medical doctors at the University of Novosibirsk in Siberia, who have now been sued by the families of 56 people whose bodies were allegedly taken without consent. The Siberian bodies were part of the contract work that Von Hagens says constitutes about 20% of the plastination done in Dalian: specimens sent by educational institutions to be plastinated for a fee and then returned. None have appeared in his exhibitions, he says. Von Hagens, who was not charged, says he was given assurances that consent had been properly obtained. Since then, he says he has refused to accept fresh, whole bodies from other institutions.

    Questions still hang over his operation, however. Officials at the Chinese Ministry of Health in Beijing, contacted by Science, said they were unaware of the work of Plastination City, which is officially listed as a “manikin company” in Dalian. Von Hagens says he did not know it was listed this way. He says he has obtained “a few” Chinese bodies through a nascent donor program he set up in Dalian. He admits to using “unclaimed” bodies provided by the Chinese government, but he says they are only for in-house “educational” purposes and that no Chinese bodies have appeared in Body Worlds.

    Although Von Hagens says he follows strict consent procedures for whole-body specimens, he maintains that “consent is not important for body parts.” Others find this view unacceptable. The Nuffield Council on Bioethics has spent years drawing up standards and ethical requirements aimed at plugging such loopholes, explains Thomas, after the revelation that in the 1990s some British hospitals had taken body parts from dead infants without consent (Science, 6 December 2002, p. 1867). “Von Hagens's posturing indicates that he takes the view that he is exempt from observing these requirements or standards.”

    Von Hagens will also have to overcome legal hurdles if he is to exhibit in the United States. The city of Munich asked him to show signed donor contracts for his plastinated cadavers, but he refused on grounds of privacy and the request was eventually dropped. But in the United States, says Wade, the Uniform Anatomical Gift Act can be used to force him to do so. And even if he does show that he has obtained informed consent, states' anatomy boards will have to give him the go-ahead based on their judgement of his intentions, says Lynn Romrell, chair of the anatomy board in Florida that blocked Von Hagens in 1998. “We decided that his intentions were not educational,” says Romrell, and it will be up to Von Hagens to convince the anatomy boards in other states.

    In spite of these barriers, Von Hagens says that his plans to conquer the United States in 2004 are “definite,” although he is keeping his intended dates and venues under wraps. An American tour is bound to be controversial, says Wade, because “this country doesn't believe that anyone's death should be used for someone else's profit.” But then again, Von Hagens is no stranger to controversy. He thrives on it.

  10. GUNTHER VON HAGENS

    Plastination: Putting a Stopper in Death

    1. John Bohannon*
    1. John Bohannon is a writer based in Paris. With reporting by Ding Yimin and Xiong Lei of China Features in Beijing.

    For those who crave physical immortality, the main obstacle has always been the inevitable process of putrefaction. To preserve their nobility, the ancient Egyptians used mummification to stave off hungry bacteria and fungi. But after the brain is yanked out through the nose, the viscera scooped out, and the rest cured with potassium nitrate, the body does not look its best.

    The pharaohs would have just loved a technique called plastination, invented by German anatomist-entrepreneur Gunther von Hagens, which not only permanently protects flesh from decay but preserves its original color and structure down to the cellular level. Whereas mainstream chemical preservation leaves the body's water in place and adds chemicals to fix the proteins of the tissue and to kill microbes, plastination replaces all the water with resilient polymers such as silicone rubber or polyester resin.

    There are many variations on plastination, depending for example on what is to be emphasized or whether the body is to be sliced into layers or exhibited whole. But the first step is always freezing the body fast enough to prevent the formation of membrane-rupturing ice crystals. The frozen cadaver is then submerged in a bath of acetone at −25°C for up to 30 days until all its water has diffused off and been replaced by acetone. Most bodies then go into another acetone bath at room temperature to dissolve away fat. The body then goes into a bath of liquid silicone under vacuum for up to 14 days, during which the acetone slowly evaporates and is replaced with silicone.

    At this point, the body is ready to be skinned, dissected, and articulated before being hardened by treatment with gas, heat, or ultraviolet light. Over 1000 hours of dedicated work and at least $30,000 go into the creation of a single whole-body specimen.

  11. SOLAR PHYSICS

    A Space Weather Aerie in the Caucasus?

    1. Richard Stone

    The enterprising director of a cosmic ray observatory in Armenia is hoping to launch a global network of ground stations that would complement space-based forecasting

    If you're in Armenia and want to catch some solar rays, try scaling the southern peak of Mount Aragats. There, 3200 meters up, an observatory run by the Cosmic Ray Division (CRD) of the Yerevan Physics Institute casts an unblinking eye on our star. Now the Soviet-era holdover is spearheading a bold new venture: a worldwide alert service that would warn of devastating solar storms approximately half an hour before their radiation blasts strike Earth's atmosphere.

    During crests in its 11-year activity cycle, the sun occasionally unleashes a violent flare often accompanied by a billion-ton burst of plasma known as a coronal mass ejection. Such solar storms have knocked out several satellites in the past 2 decades and brought down Quebec's power grid in March 1989, and they could threaten astronauts by disrupting onboard instruments or walloping them with radiation.

    Where the sun doesn't shine.

    In winter, underground tunnels are often the only way for technician Tigran Yepiscoposian and others to move between buildings.

    CREDIT: CRD

    To forecast space weather, scientists monitor the stream of ionized particles from the sun using Earth-orbiting satellites and two spacecraft—NASA's Advanced Composition Explorer (ACE) and the Solar and Heliospheric Observatory (SOHO), a joint NASA-European Space Agency mission—that pirouette in a part of our solar system where the gravitational fields of Earth and the sun roughly cancel each other out. ACE and SOHO pick up the deluge of particles that can wreak havoc on satellites and power grids.

    But many experts argue that it is risky to rely solely on satellites to flag oncoming solar storms. For one, congressional appropriators are threatening the U.S.'s premier space weather forecasting service—the National Oceanic and Atmospheric Administration's Space Environment Center (SEC), a satellite-based alert and research unit—with a 40% cut to its proposed $8.3 million budget in 2004. And the space-based sensors themselves are not fail-safe, as the recent drama surrounding SOHO demonstrated (Science, 4 July, p. 31).

    An alert system on terra firma could provide a safety net in case spaceborne sensors were to falter. “That's a valid paradigm,” says Joseph Kunches, chief of SEC's space weather operations division. In a proposal to the International Science and Technology Center (ISTC), a Moscow-based outfit that funds nonproliferation activities across the former Soviet Union, CRD director Ashot Chilingarian has outlined a novel ground-based network that would rely on the detection of high-energy particles that pelt Earth roughly 30 minutes before the brunt of a solar storm arrives. “It's a fascinating project that promises to have critical applications,” says physicist Alex Chao of the Stanford Linear Accelerator Center in Menlo Park, California.

    With a unique combination of detectors and homespun analytical software, Chilingarian's team thinks it can spot the high-energy vanguard of an oncoming solar storm reliably enough to allow operators to take precautions such as flicking electronic switches to safe mode. In its ISTC proposal, now being vetted by the U.S. Department of State, CRD aims to construct a pair of prototypes of detectors that could be deployed at stations around the world. Chilingarian has launched negotiations with space weather centers in Greece, Israel, Russia, the United States, and elsewhere to form a network for global coverage. “He's young, aggressive, and energetic. I think he can succeed,” says Yasushi Muraki of the Solar-Terrestrial Environment Laboratory at Nagoya University in Japan.

    Solar flair.

    Ashot Chilingarian hopes to secure his center's future by launching a space weather alert service.

    CREDIT: MKHITAR KHACHATRIAN/COURTESY OF THE SUPPORT COMMITTEE FOR ARMENIA'S COSMIC RAY DIVISION

    A child of the Soviet atom bomb program, CRD was founded in 1943 by two Armenian brothers, physicists Abraham and Artem Alikhanian. There were higher mountains in the Soviet Union, but Aragats was near a major city, Yerevan, and far from the war's frontlines. Before the advent of massive particle accelerators, cosmic rays were the best source of high-energy particles, and the Alikhanian brothers were “clever enough to see a connection between cosmic ray research and the theoretical research of the atomic bomb project,” says Chilingarian. Although data gathered at Aragats don't appear to have helped in the development of the Soviet atom bomb, he says, the nuclear connection allowed Artem to build an impressive cosmic ray observatory. When it came to money, the sky was the limit.

    By 1993, when Chilingarian was handed CRD's reins, state funding had all but evaporated. It's hard enough doing science at the summit: In winter, average snow depth tops 1.5 meters, and scientists are forced to scuttle from building to building through tunnels without going outdoors for days on end. Compounding their woes, their instruments were rapidly becoming antiquated. Chilingarian began a campaign to link up with other cosmic ray facilities. Drawing on his talents as a software engineer, he authored a neural network program that several multicenter collaborations use for data analysis.

    Chilingarian's latest innovation is a system linking more sensitive solar monitors with fast electronics and Global Positioning System receivers to forecast potential hazards of violent solar storms. The idea for meshing data from ground-based detectors to sound an alarm came in the 1990s from someone Chilingarian calls “a giant in the field”: Lev Dorman, head of Israel's Cosmic Ray Center in Tel Aviv and a senior figure at the Institute of Terrestrial Magnetism, Ionosphere, and Radiowave Propagation in Troitsk, Russia.

    Chilingarian's epiphany—that Dorman's concept was feasible—came on the heels of a nasty solar storm on 14 July 2000. The Aragats detectors, near the summit and at Nor Amberd station 1200 meters down the mountain, tracked fluxes in all three classes of secondary particles produced when protons and ions from the sun impinge on the atmosphere: charged particles (electrons, protons, pions, and low-energy muons), neutrons, and high-energy muons. After the data suggested that high-energy particles could serve as a harbinger of an ill solar wind, Chilingarian says, “we decided to build our monitoring system.” Although “there are several unknowns” in the relation between high-and low-energy particles, notes astronomer Vahe Petrosian of Stanford University, “none appear to be insurmountable.” Such an alert service, adds Hartmut Gemmeke, head of electronics and data processing at the Forschungszentrum Karlsruhe in Germany, would “provide a necessary source for reliable and easily accessible data.” He predicts that it will take 3 to 5 years to gather enough data to see if the system will pan out.

    National pride.

    Armenia marked CRD's 60th anniversary this year with a postage stamp.

    CREDIT: ARMENIAN POSTAL SERVICE

    “If successful,” says Chao, “this method could save satellites, power grids, and other items of interest.” Charged particles overload electrical systems with extra current, initiating fake commands, altering memory files, and burning silicon chips. Turning off electronics means that the particles “pass through silicon without any consequences,” Chilingarian explains. And most important to CRD, success as a space weather sentinel would make its services indispensable. That could prove to be the center's salvation as it struggles, in the economic wilderness of the Caucasus, to keep its finger on the solar pulse.

  12. GENOMICS

    Sequencers Examine Priorities

    1. Jennifer Couzin

    Now that genomes can be decoded quickly, researchers are debating how to choose which organisms to sequence next

    The most conspicuous feature of a recent gene-sequencing meeting in Virginia might have been what was absent: There was no verbal venom between once-cutthroat competitors. Instead, the Whitehead Institute's Eric Lander and former Celera president J. Craig Venter, their race to sequence the human genome behind them, calmly chatted away. Walking by the pair, Edward Rubin, director of the Department of Energy's (DOE's) Joint Genome Institute in Walnut Creek, California, did a double take. “Instead of shooting at each other, they're pointing their cannons in the same direction,” says Rubin.

    The invitation-only, closed-door gathering on 21 and 22 July marked a turning point in the world of gene sequencing. There, officials from the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, estimated that in the best-case scenario, over the next 4 years U.S. sequencing centers would generate a staggering 460 billion bases, the equivalent of 22 mammalian genomes. But with all the “obvious” organisms—including the human, the mouse, and the rat—now sequenced, or nearly so, the genetics community and NHGRI, its principal funder, are weighing how to proceed. The country's three massive sequencing centers, fearful of becoming mere factories churning out base after base, are lobbying to preserve influence in choosing which organisms to sequence and analyzing the genetic data they produce. Scientists who mobilized around beloved animals, from the honeybee to the chicken, and won them a spot in the sequencing queue are now wondering what they will target next.

    The 30 to 40 prominent researchers who attended the meeting, many of whom commented with surprise on its collegiality, agreed that sequencing should now be driven by biological unknowns rather than popularity contests. “We should turn to using sequencing capacity to answer scientific questions that are of seminal importance,” wrote Princeton University President Shirley Tilghman in an e-mail message. And if that means sequencing an organism “that by biologists' standard is obscure,” she added, “so be it.”

    Many participants believe that today's system for prioritizing organisms doesn't capture the most pressing scientific questions. They suggested adding a new layer of four committees to the review process to divvy up sequencing proposals according to scientific goals, such as clarifying evolution or helping shed light on the human genome. Each committee, in turn, would make funding recommendations to an existing NHGRI grant review panel.

    The tentative list of new committees includes one to advance annotation of the human genome, another to advance annotation of model organisms, a third to further evolutionary biology, and a fourth that embraces novel organisms—a final opportunity for scientists to promote their pet subjects. The plan is still rough, and the committees “are tremendous overlapping circles,” says Venter, now president and chair of the nonprofit Center for the Advancement of Genomics in Rockville, Maryland.

    Many agreed that sequencing priorities are changing and that a new approach is needed for directing the community's now massive sequencing capacity. “If I want to justify sequencing a large number of Drosophila species, I wouldn't be saying, ‘Drosophila's a great organism; there's a large community working on them,’” says Gerald Rubin, vice president of the Howard Hughes Medical Institute (HHMI) in Chevy Chase, Maryland. “I might be arguing, ‘Here's a major unsolved problem in population biology. … [With Drosophila], we can solve this problem.’” Most organisms with a fan club of more than 100 scientists have already been decoded or are well on their way, he adds. The interest now falls increasingly on comparative genomics: overlaying the genomes of multiple species to identify what's been conserved over time, what's been added, and what's been abandoned.

    Who's next?

    New criteria may determine which organisms join these ones in the sequencing queue.

    CREDITS: (TOP TO BOTTOM) ARI KORNFELD; JIM KALISCH/UNL ENTOMOLOGY; TANYA DEWEY/UNIVERSITY OF MICHIGAN MUSEUM OF ZOOLOGY

    NHGRI is tight-lipped about whether it will adopt the suggestions of the scientists it brought together. That would be “premature” to discuss, says Jane Peterson, NHGRI's program director for comparative genetics. She expects the institute's advisory council to take up the matter at its meeting in September. Above all, says Peterson, NHGRI wants to ensure that its sequencing priorities are in line with the 5-year plan it unveiled late last year (Science, 29 November 2002, p. 1694). Among the plan's most ambitious goals: to define the function of every part of the human genome.

    The role played by the sequencing centers in that process remains in contention. “I hope people are thinking of us as more than just factories,” says Richard Wilson, director of the sequencing center at Washington University in St. Louis, Missouri. (The other NHGRI-funded centers for large-scale sequencing are located at the Whitehead Institute/MIT Center for Genome Research in Cambridge and at Baylor College of Medicine in Houston.)

    View this table:

    DOE's Edward Rubin, whose center focuses on decoding microbes, agrees that the ground is beginning to shift. “There really is tension,” he says. “These people have invested a lot of their lives in setting these centers up, and then to just generate strings of A's and T's that other people consume is a difficult pill.” The tough question confronting gene sequencing efforts, he says, is, “Whose projects are they?”

    Some answers may emerge this fall. That's when NHGRI plans to announce new 3-year funding awards to large-scale sequencing centers. The institute is accepting applications beyond those from the big three, and at least a few hopefuls have applied. Among them are Venter's institute and Agencourt Bioscience Corp. in Beverly, Massachusetts.

    NHGRI isn't certain how the funding awards will stack up against preceding ones. In the 2002 fiscal year, the institute spent $190 million on large-scale sequencing projects; although the proportion of funds devoted to such work may shrink, NHGRI expects its grantees to churn out more DNA sequence than ever, thanks to declining costs.

    With input from sequencers, NHGRI is also trying to determine which method for sequencing organisms is best. “Could we make some shortcuts?” asks Eric Green, the institute's scientific director. His lab is currently assessing the virtues of draft sequences, which are far cheaper to assemble than polished genomes. Venter wryly notes that the whole-genome shotgun method favored by Celera and criticized by NHGRI in the past is now apparently being embraced (Science, 16 February 2001, p. 1182).

    The Drosophila community in particular is congregating behind a draft approach, hoping to sequence perhaps dozens of fruit fly species. “I'm completely confident that 10 years from now we'll have the sequences of 50 Drosophila,” says HHMI's Gerald Rubin. Those data could help identify hotspots in the sequence that evolved rapidly and simplify assembly of closely related genomes. NHGRI is currently considering a proposal from Drosophila geneticists to sequence eight species, at a cost of roughly $40 million. That's in addition to two that are already sequenced and two that are approved and in the pipeline.

    Implicit in the choice of which genomes to sequence lies a greater uncertainty: If genomes should be selected based on the biological mysteries they could help solve, which mysteries top the list? That was something last month's collegial meeting steered clear of. “It delayed the hard issues,” such as whether to award one vertebrate at the expense of 40 Drosophila, with their much smaller genomes, says Green. Which ones win out, at least in the short term, will be a topic for another day.

  13. PALEOANTHROPOLOGY

    Africans Begin to Make Their Mark in Human-Origins Research

    1. Ann Gibbons

    After decades of effort, a handful of black Africans are taking leadership roles in analyzing the wealth of human fossils that come from African soil

    For Berhane Asfaw, the moment was especially sweet. Like a proud father, Asfaw described to a rapt audience at an 11 June press conference in Addis Ababa how he had found the 160,000-year-old skull of a child in 200 pieces near the village of Herto in his native Ethiopia. The fossil, one of the earliest known members of our species, was featured on the cover of Nature. “For the first time, our research got maximum attention,” says Asfaw. But it was not just the find itself that made the event noteworthy: The achievement underscored the fact that Ethiopians have become major players in human-origins research.

    Most of the oldest and most important fossils of human ancestors have been unearthed in Africa, often by Africans. But until recently no black Africans led these expeditions, and few did paleoanthropology research in their own countries, despite millions spent on scholarships. When Asfaw got his Ph.D. in 1988 from the University of California, Berkeley, for example, he had few Ethiopian peers.

    Today, however, Asfaw, 50, a paleoanthropologist at the Rift Valley Research Service, works as co-leader of the international Middle Awash research project, sharing both scientific and logistic responsibilities with a tightly knit team of Ethiopians and their collaborators. The numbers are not large— Asfaw has about a dozen Ph.D.-level Ethiopian colleagues—and not all are doing research. But in the small community of human-origins researchers, they are making their mark, finding stunning fossils, publishing in top journals, and leading field expeditions. “The Ethiopians have done extraordinarily well in the past decade,” says anatomist John Fleagle of the State University of New York, Stony Brook. Similar success stories are emerging in other African nations as a new generation completes doctorates.

    Many of these pathbreaking scientists have taken jobs in the United States or Europe, because funding this type of research is a luxury for African governments fighting AIDS and famine. But some researchers return every year to do fieldwork, maintaining links with their home countries and setting an example for younger Africans. The benefits are more than scientific: Some have formed prehistory clubs to talk about evolution in local schools, and others are starting field schools. “Africans at the elite level will take more of an interest in human origins if research is being done by Africans,” says political scientist David Shinn of George Washington University in Washington, D.C., who was the U.S. ambassador to Ethiopia from 1996 to 1999.

    Educating fossil finders

    For a half-century, human-origins research was often an import-export business: Scientists were imported from Europe and the United States, and key fossils were exported from Africa. Given the expense and uncertainty of finding hominid fossils, foreigners and white Africans led the first surveys in Africa, whereas educated black Africans tended to choose to become physicians or wildlife biologists, for example, rather than paleoanthropologists. But local people did work as field assistants and museum staff, and some were fascinated by the science. Kenyan student Fredrick Kyalo Manthi remembers that his father, Anthony Manthi Mutemwa, a field assistant with the late archaeologist Mary Leakey in Tanzania, brought home books on prehistory. But Mutemwa could not afford to go to college or to send his children there.

    At the top.

    Berhane Asfaw and Tim White co-lead a field project.

    CREDIT: 1998 DAVID L. BRILL/ATLANTA

    By the late 1970s, some researchers found the situation “embarrassing,” says paleoanthropologist Tim White, one of Asfaw's Ph.D. advisers at Berkeley. Having Africans lead research is good for science, says White, because local scientists are more invested in protecting their nation's antiquities. And unless local people value them, fossils will disappear.

    Realizing this, the Leakey Foundation—a member-supported organization that funds research into human origins—in the late 1970s began granting fellowships to Africans seeking advanced degrees, says executive director Bob Lasher. Since then, the foundation has awarded 68 fellowships totaling $1.2 million, chiefly to Kenyans, Tanzanians, and Ethiopians, in that order.

    The program has a good track record: 81% of fellowship recipients are still working in related fields, with 15 holding U.S. posts and 40 or so in various jobs in Africa. But the actual number doing research is unclear. And the program has had growing pains, partly because students faced daunting obstacles of language, culture, and sometimes, limited education. By the early 1990s, some fellows were not completing their Ph.D.s, and some sponsors were not seriously committed to training, says Fleagle, a member of the foundation's scientific advisory board. As a result, the Leakey Foundation now targets the first 2 years of study and encourages universities to fund later years.

    A key lesson learned early was the importance of a strong mentor. White, for example, worked closely with Asfaw and fellow Ethiopian Yohannes Haile-Selassie, 42, while they were graduate students at Berkeley, encouraging Haile-Selassie to be sole author of a Nature paper describing important fossils he found. Haile-Selassie is now curator of physical anthropology at the Cleveland Museum of Natural History in Ohio. Others have trained successful Africans too, notably Henry de Lumley, director of the National Museum of Natural History in Paris.

    To excel in science, African researchers say it's crucial to build a community of African scholars who mentor each other and create a culture that supports high-quality research, as has happened at Berkeley. When Asfaw arrived on campus in 1980, he was one of dozens of foreign students recruited by the late prehistorian J. Desmond Clark, who already had students from Malawi, Zambia, and Nigeria. “It was Desmond's dream to have lots of Africans involved in African prehistory,” says Asfaw.

    Bridging worlds.

    Tanzanian Charles Musiba, shown with Masai elders in the field, is a professor in North Dakota.

    CREDIT: PETER HVIZDAK

    Asfaw in turn began recruiting colleagues to get Ph.D.s when he went home for field seasons, starting with his college classmate Giday WoldeGabriel, then a geology lecturer at Addis Ababa University. “I didn't want to be the only person trained in this field,” says Asfaw. Today, WoldeGabriel is a geologist at Los Alamos National Laboratory in New Mexico and returns to Ethiopia every year as co-leader for the Middle Awash research project in charge of geology. Later, Asfaw helped recruit Sileshi Semaw, 43, a research associate at Indiana University, Bloomington; and Yonas Beyene, 45, who heads the archaeology division of the Ministry of Culture in Ethiopia. Although they received their Ph.D.s from different institutions, “we work as a pack,” says Semaw. “We turn to each other to sort out problems,” such as disputes about sites or finding jobs.

    Beyond the Ph.D.

    But it's not enough to train people, says WoldeGabriel; “there has to be some kind of infrastructure [for Africans] to go back to.” And there are a few efforts to develop strong African institutions. In Ethiopia, University of Texas geologist John Kappelman is starting a geology field school, and Charles Lockwood of Arizona State University (ASU) in Tempe is seeking funds to start a research center. The respected National Museums of Kenya (NMK) is now staffed entirely by Kenyans, including some who trained at a field school at Koobi Fora and other African institutions. Of the 26 Kenyans awarded Leakey Foundation fellowships, a half-dozen returned to museum or university jobs, where they are filling “essential roles” in research, education, conservation, and public relations, says paleontologist Meave Leakey of the NMK.

    But archaeologists have fared better than paleoanthropologists, who have had more difficulty getting jobs that allow time and financing for fieldwork, says Leakey. “Of all the many students who have been supported for higher degrees in paleoanthropology, very few have actually returned to Kenya,” she says. For example, Kenyan paleontologist William Anyonge returned to a teaching job in California because he was paid too little at the NMK.

    Indeed, supporting Africans while they are students isn't enough, because the roadblocks after the Ph.D. are the most daunting, says Lasher. Many Africans want to go home to work, but there are few research jobs there. For example, when Asfaw returned to Ethiopia in the summer of 1988, he found no housing, few colleagues, and few prospects, because the government at the time had halted fossil exploration.

    And sometimes officials do not welcome returning scholars. In Tanzania, one official in the antiquities department blocked the hiring of new Ph.D.s, says Charles Musiba, 43, a Tanzanian paleoanthropologist at North Dakota State University in Fargo. That official was fired in the 1990s, but “he put Tanzania 15 years behind other countries,” says Musiba. As a result, many Africans end up staying abroad—the classic brain drain problem.

    The reasons are complex. “Most persons who have studied the brain drain phenomenon have concluded that it is not realistic to expect a significant percentage to return many years later,” says Shinn. “Only after African economies become much stronger and the political situation improves substantially will [that] be possible.”

    Yet even though many African scientists are based outside Africa, many try to spend several months a year searching for fossils there. Thus they serve as a bridge between the international scientific establishment and the nascent institutions of their own countries, where they also focus on building labs and libraries and recruiting colleagues. For now, “the best position is to be in both places,” says Zeresenay Alemseged, 34, an Ethiopian postdoc at ASU's Institute of Human Origins, who got his Ph.D. at the University of Paris. “It's good to publish papers in Nature or Science, but we also have to make sure we're the bridge to the future in African paleoanthropology.”

    And despite past problems, Leakey has high hopes for the dozen Kenyans earning Ph.D.s now, several of whom already have good prospects for working as paleoanthropologists. “I am really hoping this current bunch will change the negative trend,” she says.

    Career in hand.

    Emma Mbua plans to return to Kenya after a postdoc at Berkeley.

    CREDIT: HENRY GILBERT

    For example, Manthi, 36, is fulfilling his father's dream with help from the Leakey Foundation and geologist Frank Brown of the University of Utah in Salt Lake City, who helped pay his tuition. Manthi is earning his Ph.D. at the University of Cape Town in South Africa, has discovered a hominid skull in Kenya, and has started a local prehistory club there. “He's a real charger,” says Lasher. Emma Mbua, 48, earned her Ph.D. at the University of Hamburg, Germany, while working her way up at the NMK to head of paleontology. Now on leave as a postdoc with White at Berkeley, she plans to return to her job and find her own site in Kenya.

    In Tanzania, anatomist Cassian Magori of the University of Dar es Salaam and Musiba are co-leaders of the Tanzanian School for Paleoanthropology, in its third year training Tanzanian and American students at a field school at the famous Laetoli fossil beds. “Tanzania has so many archaeological sites, and we're trying to bring back paleoanthropological research,” says Musiba.

    To judge from the Ethiopian example, the contributions of even a few scientists can have a major impact in their homeland. In the 1990s, when the Middle Awash team found remarkable fossils, government officials didn't even come to the press conferences. But in June, Ethiopian minister of culture Teshome Toga organized the conference and made the announcement. Vice minister of information Netsanet Asfaw (no relation to Berhane Asfaw) sat in the audience, beaming. Their presence signaled that a growing number of Ethiopians appreciate research on prehistory and the scholars who do it. “They are making Ethiopia known in a positive way,” said Netsanet Asfaw. “We feel very proud and happy. This is very, very important for our country.”

Log in to view full text